Two European case studies have provided insight into how viral and host factors determine the severity of primary HIV infection and early response to treatment. While the study of virus–host interactions is in its infancy and many questions remain, the reports in the journals Clinical Infectious Diseases and AIDS support the growing evidence that HLA type may play a role in determining host response.
HIV disease progression depends on many factors—some related to the virus and some related to the host. Knowing more about these factors could have many implications, from tailoring antiretroviral treatment to identifying potential targets for prevention efforts. However, it has been difficult to tease apart the multitude of factors involved. In clinical case studies of real-life situations, two research groups from Europe have identified at least some of the viral and host factors acting during primary HIV infection.
Severe acute HIV infection
In an article in the January 15th edition of Clinical Infectious Diseases, Spanish investigators report two cases of severe HIV infection progressing directly to AIDS while the patients had immunological markers of acute infection. Investigators were also able to identify the sexual partner who was the source of HIV infection in one of the cases.
HIV isolated from all patients produced signs of aggressive infection in test tube assays. The virus replicated very efficiently and was able to infect cells expressing CCR5 or CXCR4 co-receptors. CXCR4-infecting virus has been linked to advanced HIV disease. What’s more, the virus isolated in case 2 was subtype CRF02-AG, which is rare in Spain but common in West Africa and western Central Africa. The investigators write that its presence in this severe case “raises concerns about its superior replication fitness and/or transmission efficiency”.
Investigators then analysed the patients for factors that may have made them more susceptible to rapid disease progression. Human leukocyte antigen (HLA) class I is a group of proteins that play a role in the immune system’s response to infections, including HIV. Certain versions of HLA have been associated with a slower or more rapid progression of HIV disease. Upon analysis, the patient in case 1 expressed the specific HLA type HLA-B*3503, which has been reported to increase the risk of disease progression.
The immune response to viral infections like HIV includes the activation of CD8 cells, also called cytotoxic T lymphocytes, however this response can sometimes fail either due to malfunction of the system or due to escape mutations developed by the virus. In in vitro tests, patient 1 showed a widespread inability to mount an adequate response HIV and another virus, Epstein Barr virus, suggesting an inherent defect in the immune response. In case 2, there was some evidence that the lack of response may have been due to escape mutations in the virus, but the investigators could not rule out a potential defect in the patient’s immune system.
Antiretroviral therapy during acute infection
In a research letter published in the January 14th edition of AIDS, German researchers describes a cluster of four people in which genetic analysis of viral genomes suggested that one source person, patient A, infected two others, patients B and C, during sex. Patient C then transmitted HIV to a fourth person, patient D. The viral genetic sequence was nearly identical between patients, with 99.6% of the genome being the same in all four isolates, suggesting transmission occurred over a short period.
As part of an acute infection treatment strategy, all patients received antiretroviral therapy for six months and all achieved an undetectable viral load. Six months after therapy was stopped, patients’ viral loads rose, with patients A and C reporting relatively high viral set points (90,000 and 600,000 copies/ml, respectively) and patients B and D reporting lower set points (7000 and 33,000 copies/ml, respectively).
With nearly identical virus, the investigators reasoned that differences in responses could be ascribed to host factors, so they then analysed several markers of immune function in the four patients. They noted that patient B carried a potentially protective version of the CCR5 receptor gene. Further more, patients B and D had versions of HLA associated with better disease control (HLA-B57 and HLA-A11, respectively). The investigators say that their data suggest that these and other host immune factors had a strong impact on the control of viral replication following cessation of therapy.
The German study was conducted in the context of antiretroviral therapy during acute HIV infection, which has yet to show concrete benefit in clinical trials, and in conclusion investigators comment that host factors such as presence of HLA-B57 should be included in trials of acute infection therapy so that the relative contribution of each can be better defined.
Dalmau J et al. Contribution of immunological and virological factors to extremely severe primary HIV type 1 infection. Clin Infect Dis 48: 229 – 238, 2009.
Streeck H et al. Epidemiologically linked transmission of HIV-1 illustrates the impact of host genetics on virological outcome. AIDS 23: 259 – 262, 2009.